Phosphodiesterase expression during the progression of prostate cancer: the significance of PDE4D7

Henderson, David James Peter (2012) Phosphodiesterase expression during the progression of prostate cancer: the significance of PDE4D7. PhD thesis, University of Glasgow.

Abstract

3',5'-cyclic adenosine monophosphate (cAMP) is an important second messenger molecule involved in various signalling responses. cAMP signalling is balanced by the activity of adenylyl cyclase enzymes which catalyse the formation of cAMP from ATP, and the activity of phosphodiesterase enzymes (PDEs) which represent the only means by which cAMP is degraded. A complex balance of synthesis and degradation is underpinned by the expression of multiple cAMP PDE families and splice variants. This allows the cell type secific targeting of PDE isoforms to discreet intracellular signalling complexes. The outcome of this differential patterning of expression is a dynamic and compartmentalised web of cyclic nucleotide gradients that modulate responses to extra-cellular stimuli. Compartmentalization of signalling cascades and cAMP gradients allow multiple differing signal transduction events to occur simultaneously and controls cAMP signalling in time and space within the crowded milieu of intracellular molecular interaction.
The PDE isoform expression pattern within human prostate tumours has never been fully described. I have addressed this by reporting a PDE profile for 10 androgen-sensitive and 9 androgen-insensitive cell lines and xenografts. I describe that the PDE4D sub-family is dysregulated in androgen independent disease. In particular I show that the PDE4D isoforms PDE4D3, PDE4D4 and PDE4D7 are significantly down-regulated. PDE4D7 was observed to contribute the largest degree of expression and most dramatic down-regulation of any PDE4 isoform and was therefore chosen for further study.
Within this thesis, I describe my efforts to characterise PDE4D7 in the context of the human prostate. I describe its sub-cellular localisation and show it contributes a significant proportion of rolipram sensitive PDE activity at the plasma membrane of AS VCaP cells. The transcriptional regulation of PDE4D7 was also investigated and I found that PDE4D7 is regulated independently of the androgen signalling axis, and that it's genetic overlap with PART-1 poses intriguing possibilities for further research.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Due to copyright and IP restrictions the full text of this thesis cannot be made available online. Access to the printed version is available once any embargo periods have expired.
• Keywords: Prostate Cancer, Phosphodiesterases, cAMP
• Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Supervisor's Name: Houslay, Prof. Miles D. and Ralf, Dr. Hoffmann
• Date of Award: 2012
• Depositing User: Dr David J P Henderson
• Unique ID: glathesis:2012-3120
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 17 Jan 2012
• Last Modified: 15 Jun 2016 13:41
• URI: https://theses.gla.ac.uk/id/eprint/3120